SDH-Deficient GIST

Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma with approximatley 5,000 new cases diagnosed annually in the U.S. Among these, succinate dehydrogenase (SDH)-deficient GISTs comprise only about 5-7%. SDH-deficient patients may experience only GIST tumors. However, they can also present in the setting of Carney-Stratakis Dyad (Familial paraganglioma and GIST) or Carney Triad (paraganglioma/pheochromocytoma, GIST, and pulmonary chondroma). At present, all FDA-approved anti-GIST therapies are predicated primarily upon targeting KIT and aren't effective for those with SDH gene mutations or dysfunction. Identifying an effective means of targeting SDH-deficient GIST in a novel fashion is of critical importance to patients. One of the major impediments to SDH research is the lack of a cell lines and models that could be used to study the effects of anticancer compounds and drugs on the tumor cells.

Current treatment strategies for GIST typically utilize a “one size fits all” approach, in which every GIST patient is treated with the same regimen of surgery, if applicable, and imatinib. This strategy fails to take into account the underlying genetic and molecular differences between different types of GIST. As a result, SDH-deficient GIST patients are frequently treated with TKIs with a high rate of primary drug resistance. Drs. Sicklick & Tamayo propose to model and characterize the metabolic and molecular properties of SDH-deficient GIST cells in order to develop treatment strategies. They believe that this approach could result in more favorable outcomes for all SDH-deficient GIST patients, including those with paragangliomas caused by Carney-Stratakis Dyad and Carney Triad.

SDH-Deficient Pheochromocytoma and Paraganglioma

SDH deficient paraganglioma-pheochromocytoma is an inherited condition. Paraganglia are groups of non-neuronal cells that are found near nerve cell bunches called ganglia. A tumor involving the paraganglia is known as a paraganglioma. A type of paraganglioma known as a pheochromocytoma develops in the adrenal glands, which are located on top of each kidney and produce hormones in response to stress. Other types of paragangliomas can also delelop in the head, neck, or trunk. People with hereditary paraganglioma-pheochromocytoma are susceptable to development types of paragangliomas, which may include pheochromocytomas. In the case of Carney-Stratakis dyad, patients may develop paragangliomas as well as GIST tumors.

Pheochromocytomas and some paragangliomas are associated with ganglia of the sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body due to hormones released in response to stress. Sympathetic paragangliomas found outside the adrenal glands, usually in the abdomen, are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating.

Most paragangliomas are associated with ganglia of the parasympathetic nervous system, which controls involuntary body functions such as digestion and saliva formation. Parasympathetic paragangliomas, typically found in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as coughing, hearing loss in one ear, or difficulty swallowing.

Although some paragangliomas and pheochromocytomas are noncancerous, some can metastasize to other parts of the body. Extra-adrenal paragangliomas associated with the presence of an SDH gene mutation have a more malignant potential than other types of paraganglioma or pheochromocytoma. Patients who’ve had a tumor should be monitored yearly in case of metastasizes. Hereditary paraganglioma-pheochromocytoma is typically diagnosed in a person's 30s. Hereditary paraganglioma-pheochromocytoma occurs in approximately 1 in 1 million people.

Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.

Paragangliomas and pheochromocytomas can occur in individuals with other inherited disorders, such as von-Hippel Lindau syndrome and certain types of multiple endocrine neoplasia. These other disorders feature additional tumor types and have different genetic causes. Some paragangliomas and pheochromocytomas occur in people with no history of the tumors in their families and appear not to be inherited. These cases are designated as sporadic.

In accordance with its Mission to advance treatment for SDH-deficient cancers, the SDH Cancer Research Advocates (SDH-RA) facilitates transfer of SDH-deficient tumor samples to researchers and provides a portal for those wishing to donate to SDH-deficient cancer research.

Our Featured Researchers

Jason Sicklick, MD

Dr. Jason Sicklick, MD (Principal Investigator) is an Associate Professor of Surgery and Surgical Oncology at the Moores UCSD Cancer Center. His lab uses cells lines, as well as transgenic and xenograft models of GIST to understand the biology of the disease and to test novel approaches to overcome drug-resistance. Dr. Sicklick will be responsible for the overall experimental activity of the SDH-deficient GIST study and will oversee communication of the research team. He will supervise all aspects of the proposed research, including data analysis and interpretation.

Arthur S. Tischler, MD

Dr. Arthur Tischler is a professor of pathology at Tufts University School of Medicine and senior pathologist at Tufts Medical Center, specializing in endocrine pathology. His particular clinical and research interests combine surgical pathology of pheochromocytomas and extra-adrenal paragangliomas, with cellular and molecular studies aimed at determining mechanisms that regulate tumor development and phenotype. He served as president of the Endocrine Pathology Society from 2001-2002 and editor-in-chief of the Journal Endocrine Pathology from 2002-2008. He was a founding member of the international pheochromocytoma research consortium, PRESSOR, and currently co-chairs the PRESSOR Tumor Models working group.